Subject(s)
Behcet Syndrome , Dyspnea , Humans , Behcet Syndrome/diagnosis , Behcet Syndrome/complications , Dyspnea/etiology , Dyspnea/diagnosis , Male , Adult , Female , Tomography, X-Ray Computed , Middle AgedABSTRACT
COVID-19 and infectious diseases have been included in strategic development goals (SDG) of United Nations (UN). The CD147 receptor is one of several receptors for the SARS-CoV-2 spike protein that could mediate Covid-19 viral infection of host cells. It has been recently proposed to regulate viral invasion and dissemination among lymphocytes and progenitor/stem cells. A soluble by-product of CD147 (sCD147) exists in plasma and has been previously identified as a marker of diabetes and platelet activation. We examined plasma sCD147 levels in 161 Covid-19 patients at hospital admission. We demonstrated significantly higher plasma sCD147 levels in Covid-19 patients, which correlated with plasma multiorgan dysfunction biomarkers interleukin-6, creatinine and Troponin I. Importantly, sCD147 admission levels were associated with Covid-19 severity and survival, carrying potential value as a biomarker in hospitalized patients with Covid-19 infection.
Subject(s)
COVID-19 , Spike Glycoprotein, Coronavirus , Humans , Biomarkers , Hospital Mortality , Patient Acuity , SARS-CoV-2ABSTRACT
Pulmonary arterial hypertension associated with schistosomiasis (SchPAH) and pulmonary arterial hypertension associated with portal hypertension (PoPAH) are lung diseases that develop in the presence of liver diseases. However, mechanistic pathways by which the underlying liver conditions and other drivers contribute to the development and progression of pulmonary arterial hypertension (PAH) are unclear for both etiologies. In turn, these unknowns limit certainty of strategies to prevent, diagnose, and reverse the resultant PAH. Here we consider specific mechanisms that contribute to SchPAH and PoPAH, identifying those that may be shared and those that appear to be unique to each etiology, in the hope that this exploration will both highlight known causal drivers and identify knowledge gaps appropriate for future research. Overall, the key pathophysiologic differences that we identify between SchPAH and PoPAH suggest that they are not variants of a single condition.
Subject(s)
COVID-19 , Hypertension, Pulmonary , Humans , Brazil/epidemiology , Hypertension, Pulmonary/epidemiology , PandemicsABSTRACT
Rationale: Post-coronavirus disease 2019 (COVID-19) survivors frequently have dyspnoea that can lead to exercise intolerance and lower quality of life. Despite recent advances, the pathophysiological mechanisms of exercise intolerance in the post-COVID-19 patients remain incompletely characterised. The objectives of the present study were to clarify the mechanisms of exercise intolerance in post-COVID-19 survivors after hospitalisation. Methods: This prospective study evaluated consecutive patients previously hospitalised due to moderate-to-severe/critical COVID-19. Within mean±sd 90±10â days of onset of acute COVID-19 symptoms, patients underwent a comprehensive cardiopulmonary assessment, including cardiopulmonary exercise testing with earlobe arterialised capillary blood gas analysis. Measurements and main results: 87 patients were evaluated; mean±sd peak oxygen consumption was 19.5±5.0â mL·kg-1·min-1, and the tertiles were ≤17.0, 17.1-22.2 and ≥22.3â mL·kg-1·min-1. Hospitalisation severity was similar among the three groups; however, at the follow-up visit, patients with peak oxygen consumption ≤17.0â mL·kg-1·min-1 reported a greater sensation of dyspnoea, along with indices of impaired pulmonary function, and abnormal ventilatory, gas-exchange and metabolic responses during exercise compared to patients with peak oxygen consumption >17â mL·kg-1·min-1. By multivariate logistic regression analysis (receiver operating characteristic curve analysis) adjusted for age, sex and prior pulmonary embolism, a peak dead space fraction of tidal volume ≥29 and a resting forced vital capacity ≤80% predicted were independent predictors of reduced peak oxygen consumption. Conclusions: Exercise intolerance in the post-COVID-19 survivors was related to a high dead space fraction of tidal volume at peak exercise and a decreased resting forced vital capacity, suggesting that both pulmonary microcirculation injury and ventilatory impairment could influence aerobic capacity in this patient population.
ABSTRACT
COVID-19 infection primarily targets the lungs, which in severe cases progresses to cytokine storm, acute respiratory distress syndrome, multiorgan dysfunction, and shock. Survivors are now presenting evidence of cardiopulmonary sequelae such as persistent right ventricular dysfunction, chronic thrombosis, lung fibrosis, and pulmonary hypertension. This review will summarize the current knowledge on long-term cardiopulmonary sequelae of COVID-19 and provide a framework for approaching the diagnosis and management of these entities. We will also identify research priorities to address areas of uncertainty and improve the quality of care provided to these patients.
ABSTRACT
Pulmonary arterial hypertension is an incurable disease marked by dysregulated metabolism, both at the cellular level in the pulmonary vasculature, and at the whole-body level characterized by impaired exercise oxygen consumption. Though both altered pulmonary vascular metabolism and abnormal exercise physiology are key markers of disease severity and pulmonary arterial remodeling, their precise interactions are relatively unknown. Herein we review normal pulmonary vascular physiology and the current understanding of pulmonary vascular cell metabolism and cardiopulmonary response to exercise in Pulmonary arterial hypertension. We additionally introduce a newly developed international collaborative effort aimed at quantifying exercise-induced changes in pulmonary vascular metabolism, which will inform about underlying pathophysiology and clinical management. We support our investigative approach by presenting preliminary data and discuss potential future applications of our research platform.
ABSTRACT
BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) affects tens of millions worldwide; the causes of exertional intolerance are poorly understood. The ME/CFS label overlaps with postural orthostatic tachycardia (POTS) and fibromyalgia, and objective evidence of small fiber neuropathy (SFN) is reported in approximately 50% of POTS and fibromyalgia patients. RESEARCH QUESTION: Can invasive cardiopulmonary exercise testing (iCPET) and PGP9.5-immunolabeled lower-leg skin biopsies inform the pathophysiology of ME/CFS exertional intolerance and potential relationships with SFN? STUDY DESIGN AND METHODS: We analyzed 1,516 upright invasive iCPETs performed to investigate exertional intolerance. After excluding patients with intrinsic heart or lung disease and selecting those with right atrial pressures (RAP) <6.5 mm Hg, results from 160 patients meeting ME/CFS criteria who had skin biopsy test results were compared with 36 control subjects. Rest-to-peak changes in cardiac output (Qc) were compared with oxygen uptake (Qc/VO2 slope) to identify participants with low, normal, or high pulmonary blood flow by Qc/VO2 tertiles. RESULTS: During exercise, the 160 ME/CFS patients averaged lower RAP (1.9 ± 2 vs 8.3 ± 1.5; P < .0001) and peak VO2 (80% ± 21% vs 101.4% ± 17%; P < .0001) than control subjects. The low-flow tertile had lower peak Qc than the normal and high-flow tertiles (88.4% ± 19% vs 99.5% ± 23.8% vs 99.9% ± 19.5% predicted; P < .01). In contrast, systemic oxygen extraction was impaired in high-flow vs low- and normal-flow participants (0.74% ± 0.1% vs 0.88 ± 0.11 vs 0.86 ± 0.1; P < .0001) in association with peripheral left-to-right shunting. Among the 160 ME/CFS patient biopsies, 31% were consistent with SFN (epidermal innervation ≤5.0% of predicted; P < .0001). Denervation severity did not correlate with exertional measures. INTERPRETATION: These results identify two types of peripheral neurovascular dysregulation that are biologically plausible contributors to ME/CFS exertional intolerance-depressed Qc from impaired venous return, and impaired peripheral oxygen extraction. In patients with small-fiber pathology, neuropathic dysregulation causing microvascular dilation may limit exertion by shunting oxygenated blood from capillary beds and reducing cardiac return.
Subject(s)
Exercise Test/methods , Fatigue Syndrome, Chronic/physiopathology , Small Fiber Neuropathy/physiopathology , Biopsy , Female , Humans , Male , Middle Aged , PhenotypeABSTRACT
BACKGROUND: Pulmonary arterial hypertension (PAH) is associated with increased right ventricular (RV) afterload, RV dysfunction and decreased peak oxygen uptake (pVO2). However, the pulmonary hemodynamic mechanisms measured by exercise right heart catheterization (RHC) that contribute to reduced pVO2 in idiopathic PAH (IPAH) are not completely characterized. Therefore, we sought to evaluate the exercise RHC determinants of pVO2 in patients with IPAH. METHODS: 519 consecutive patients with suspected and/or confirmed pulmonary hypertension were prospectively screened to identify 20 patients with IPAH. All IPAH patients were prospectively evaluated with resting and exercise RHC and cardiopulmonary exercise testing. RESULTS: 85% of the patients were female; the median age was 34[29-42] years old. At peak exercise, mean pulmonary arterial (PA) pressure was 76 ± 17 mmHg, PA wedge pressure was 14 ± 5 mmHg, cardiac output (CO) was 5.7 ± 1.9 L/min, pulmonary vascular resistance was 959 ± 401 dynes/s/cm5 and PA compliance was 0.9[0.6-1.2] ml/mmHg. On univariate analysis, pVO2 positively correlated to peak CO, peak cardiac index, peak stroke volume index, peak RV stroke work index (RVSWI) and peak oxygen saturation. There was a negative correlation between pVO2 and Δ (rest to peak change) PA compliance. In age-adjusted multivariate model, peak RVSWI (Coefficient = 0.15, Beta = 0.63, 95% CI [0.07-0.22], p < 0.01) and ΔPA compliance (Coefficient = -2.51, Beta = -0.43, 95% CI [-4.34-(-0.68)], p = 0.01) had the best performance predicting pVO2 (R2 = 0.66). CONCLUSIONS: In conclusion, a load dependent measurement of RV function (RVSWI) and the pulsatile component of RV afterload (ΔPA compliance) significantly influence pVO2 in IPAH, further highlighting the pivotal role of hemodynamic coupling to IPAH exercise capacity.
Subject(s)
Hypertension, Pulmonary , Ventricular Dysfunction, Right , Adult , Familial Primary Pulmonary Hypertension/diagnostic imaging , Female , Humans , Hypertension, Pulmonary/diagnostic imaging , Male , Oxygen , Pulmonary Artery/diagnostic imaging , Ventricular Dysfunction, Right/diagnostic imaging , Ventricular Function, RightABSTRACT
BACKGROUND: Right ventricular (RV) dysfunction is associated with poorer outcomes in heart failure with preserved ejection fraction (HFpEF). Although female subjects are more likely to have HFpEF, male subjects have worse prognosis and resting RV function. The contribution of dynamic RV-pulmonary arterial (RV-PA) coupling between sex and its impact on peak exercise capacity (VO2) in HFpEF is not known. RESEARCH QUESTION: The goal of this study was to investigate the differential effects of sex on RV-PA coupling during maximum incremental exercise in patients with HFpEF. STUDY DESIGN AND METHODS: This study examined rest and exercise invasive pulmonary hemodynamics in 22 male patients with HFpEF and 27 female patients with HFpEF. To further investigate the discrepancy in RV-PA response between sex, 26 age-matched control subjects (11 male subjects and 15 female subjects) were included. Single beat analysis of RV pressure waveforms was used to determine the end-systolic elastance (Ees) and pulmonary arterial elastance. RV-PA coupling was determined as the ratio of end-systolic elastance/PA elastance. RESULTS: Both HFpEF groups experienced decreased peak VO2 (% predicted). However, male patients with HFpEF experienced a greater decrement in peak VO2 compared with female patients (58 ± 16% vs 70 ± 15%; P < .05). Male patients with HFpEF had a more pronounced increase in RV afterload, Ea (1.8 ± 0.6 mm Hg/mL/m2 vs 1.3 ± 0.4 mm Hg/mL/m2; P < .05) and failed to increase RV contractility during exercise, resulting in dynamic RV-PA uncoupling (0.9 ± 0.4 vs 1.2 ± 0.4; P < .05) and subsequent reduced stroke volume index augmentation. In contrast, female patients with HFpEF were able to augment RV contractility in the face of increasing afterload, preserving RV-PA coupling during exercise. INTERPRETATION: Male patients with HFpEF were more compromised regarding dynamic RV-PA uncoupling and reduced peak VO2 compared with female patients. This finding was driven by both RV contractile impairment and afterload mismatch. In contrast, female patients with HFpEF had preserved RV-PA coupling during exercise and better peak exercise VO2 compared with male patients with HFpEF.
Subject(s)
Exercise Tolerance/physiology , Heart Failure/epidemiology , Heart Ventricles/physiopathology , Pulmonary Artery/physiopathology , Stroke Volume/physiology , Ventricular Function, Right/physiology , Ventricular Pressure/physiology , Aged , Cardiac Catheterization , Echocardiography , Female , Follow-Up Studies , Heart Failure/diagnosis , Heart Failure/physiopathology , Heart Ventricles/diagnostic imaging , Humans , Incidence , Male , Pulmonary Wedge Pressure/physiology , Retrospective Studies , Sex Distribution , Sex Factors , Systole , United States/epidemiology , Vascular ResistanceSubject(s)
Pulmonary Arterial Hypertension , Schistosomiasis , Hemodynamics , Humans , Vascular ResistanceABSTRACT
OBJECTIVE: Exercise intolerance is a common clinical manifestation of CTD. Frequently, CTD patients have associated cardio-pulmonary disease, including pulmonary hypertension or heart failure that impairs aerobic exercise capacity (pVO2). The contribution of the systemic micro-vasculature to reduced exercise capacity in CTD patients without cardiopulmonary disease has not been fully described. In this study, we sought to examine the role of systemic vascular distensibility, α in reducing exercise capacity (i.e. pVO2) in CTD patients. METHODS: Systemic and pulmonary vascular distensibility, α (%/mmHg) was determined from multipoint systemic pressure-flow plots during invasive cardiopulmonary exercise testing with pulmonary and radial arterial catheters in place in 42 CTD patients without cardiopulmonary disease and compared with 24 age and gender matched normal controls. RESULTS: During exercise, systemic vascular distensibility, α was reduced in CTD patients compared with controls (0.20 ± 0.12%/mmHg vs 0.30 ± 0.13%/mmHg, P =0.01). The reduced systemic vascular distensibility α, was associated with impaired stroke volume augmentation. On multivariate analysis, systemic vascular distensibility, α was associated with a decreased exercise capacity (pVO2) and decreased systemic oxygen extraction. CONCLUSION: Systemic vascular distensibility, α is associated with impaired systemic oxygen extraction and decreased aerobic capacity in patients with CTD without cardiopulmonary disease.
Subject(s)
Connective Tissue Diseases/physiopathology , Exercise Tolerance/physiology , Microvessels/physiopathology , Connective Tissue Diseases/complications , Dyspnea/etiology , Dyspnea/physiopathology , Elasticity , Exercise Test , Female , Humans , Male , Middle Aged , Oxygen/metabolismABSTRACT
BACKGROUND AND OBJECTIVE: Peak oxygen consumption (pVO2 ), determined from CPET, provides a valuable indication of PAH severity and patient prognosis. However, CPET is often contraindicated in severe PAH and frequently terminated prior to achievement of a sufficient exercise effort. We sought to determine whether in PAH low-intensity [i.e. freewheeling exercise (FW)] exercise reveals abnormal VE /VCO2 and PET CO2 responses that are associated with pVO2 and serve as indices of PAH risk stratification and mortality. METHODS: Retrospective analysis of CPET from 97 PAH patients and 20 age-matched controls was undertaken. FW VE /VCO2 and PET CO2 were correlated with pVO2 % age-predicted. Prognostication analysis was conducted using pVO2 > 65% age-predicted, as known to represent a low mortality risk. Primary outcome was mortality from any cause. RESULTS: FW PET CO2 was correlated with pVO2 (P < 0.0001; r = 0.52), while FW VE /VCO2 was not (P = 0.13; r = -0.16). ROC curve analyses showed that FW PET CO2 (AUC = 0.659), but not FW VE /VCO2 (AUC = 0.587), provided predictive information identifying pVO2 > 65% age-predicted (best cut-off value of 28 mm Hg). By Cox analysis, FW PET CO2 < 28 mm Hg remained a predictor of mortality after adjusting for age and PAH aetiology (HR: 2.360, 95% CI: 1.144-4.866, P = 0.020). CONCLUSION: Low PET CO2 during FW is associated with reduced pVO2 in PAH and provides predictive information for PAH risk stratification and prognostication.
Subject(s)
Familial Primary Pulmonary Hypertension/physiopathology , Pulmonary Arterial Hypertension , Exercise Test , Humans , Retrospective Studies , Risk AssessmentABSTRACT
Pulmonary arterial hypertension (PAH) is a disease of the lung blood vessels that results in right heart failure. PAH is thought to occur in about 5% to 10% of patients with hepatosplenic schistosomiasis, particularly due to S. mansoni. The lung blood vessel injury may result from a combination of embolization of eggs through portocaval shunts into the lungs causing localized Type 2 inflammatory response and vessel remodeling, triggering of autonomous pathology that becomes independent of the antigen, and high cardiac output as seen in portopulmonary hypertension. The condition is likely underdiagnosed as there is little systematic screening, and risk factors for developing PAH are not known. Screening is done by echocardiography, and formal diagnosis requires invasive right heart catheterization. Patients with Schistosoma-associated PAH show reduced functional capacity and can be treated with pulmonary vasodilators, which improves symptoms and may improve survival. There are animal models of this disease that might help in understanding disease pathogenesis and identify novel targets to screen and treatment. Pathogenic mechanisms include Type 2 immunity and activation and signaling in the TGF-ß pathway. There are still major uncertainties regarding Schistosoma-associated PAH development, course and treatment.
Subject(s)
Pulmonary Arterial Hypertension/pathology , Schistosoma mansoni/immunology , Schistosomiasis mansoni/pathology , Animals , Humans , Lung/immunology , Lung/pathology , Pulmonary Arterial Hypertension/immunology , Schistosomiasis mansoni/immunology , Transforming Growth Factor beta/immunology , Vascular Remodeling/immunology , Vascular Remodeling/physiologyABSTRACT
Pulmonary hypertension is a progressive disease whose survival is linked to adequate right ventricle adaptation to its afterload. In the current study, we performed an in-depth characterization of right ventricle function during maximum incremental exercise in patients with pulmonary hypertension and how it relates to exercise capacity. A total of 377 pulmonary hypertension patients who completed a maximum symptom-limited invasive cardiopulmonary exercise testing were evaluated to identify 45 patients with heart failure with preserved ejection fraction, 48 with exercise pulmonary hypertension, and 47 with established pulmonary arterial hypertension. These patients were compared to 17 age- and gender-matched normal controls. Load-adjusted right ventricle function was quantified as the ratio of right ventricle stroke work index to pulmonary arterial elastance. All patients with pulmonary hypertension had reduced peak VO2 %predicted compared to controls. Right ventricle function deteriorated for all pulmonary hypertension groups by 50% of peak VO2. Worsening of right ventricle function during freewheeling exercise was associated with greater reduction in peak VO2 compared to those whose right ventricle function deteriorated at later exercise stages (i.e. min 1, 2, and 3). On multivariate analysis, reduced ratio of right ventricle stroke work index to arterial elastance was an independent predictor of peak VO2 %predicted (ß-Coefficient -5.46, 95% CI: -9.47 to -1.47, p = 0.01). Right ventricle function deteriorates early during incremental exercise in pulmonary hypertension, occurring by 50% of peak oxygen uptake. The current study demonstrates that right ventricle dysfunction is an early phenomenon during incremental exercise in pulmonary hypertension, occurring by 50% of peak oxygen uptake. The threshold at which right ventricle function is compromised during incremental exercise in pulmonary hypertension influences aerobic capacity and may help guide exercise strategies to mitigate dynamic worsening of right ventricle function during exercise training.